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Akt1 governs breast cancer progression in vivo

Xiaoming Ju1, Sanjay Katiyar, Chenguang Wang

  • 1Department of Cancer Biology, Kimmel Cancer Center, Thomas Jefferson University, 233 South 10th Street, Philadelphia, PA 19107, USA.

Proceedings of the National Academy of Sciences of the United States of America
|April 27, 2007
PubMed

Insights

The serine threonine kinase Akt1 is crucial for ErbB2-induced breast cancer development. Disabling Akt1 in mice slowed tumor growth and reduced metastasis by affecting cell growth and migration.

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Cell Biology

Background:

  • The serine threonine kinase Akt1 plays a role in cellular metabolism, survival, and growth.
  • Akt1 is a member of the Akt gene family, ubiquitously expressed in mammals.

Purpose of the Study:

  • To investigate the role of Akt1 in ErbB2-induced mammary tumorigenesis.
  • To elucidate the mechanisms by which Akt1 influences tumor cell behavior and metastasis.

Main Methods:

  • Disruption of the Akt1 gene in mice.
  • Analysis of tumor growth, metastasis, and phosphorylation of Akt1 targets (e.g., TSC2).
  • Characterization of mammary epithelial tumor cells (MEC) in vitro (3D culture) and in vivo.
  • Assessment of cell size, proliferation, protein abundance (cyclin D1, p27KIP1), cell polarity, and migration.
  • Unbiased proteomic analysis to identify signaling pathways involved in Akt1-mediated migration.

Main Results:

  • Akt1 deficiency delayed tumor growth and reduced lung metastases in a mouse model of ErbB2-induced mammary cancer.
  • Akt1 deficiency reduced phosphorylation of TSC2 at Ser-939, decreased MEC size and proliferation, and altered cyclin D1 and p27KIP1 levels.
  • Akt1 was essential for oncogene-induced changes in MEC polarity and migration, including relocalization of phosphorylated ezrin-radixin-moesin proteins.
  • Akt1 promoted MEC migration and directional persistence via paracrine signaling, inducing expression and secretion of CXCL16 and MIP1gamma.

Conclusions:

  • Akt1 is required for ErbB2-induced mammary tumorigenesis in vivo.
  • Akt1 governs MEC polarity, migratory directionality, and breast cancer onset.
  • Targeting Akt1 may represent a therapeutic strategy for ErbB2-driven breast cancers.

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